Targacept active conformation search: a new method for predicting the conformation of a ligand bound to its protein target.

Targacept active conformation search (TACS) is a novel variation of well-established three-dimensional quantitative structure--activity relationship methodologies that seeks to determine probable conformation(s) of ligands bound to their protein targets. A combination of affinity or activity data and energetically accessible conformational ensembles, each conformer described by three-dimensional (3-D) sensitive descriptors, forms the basis of the TACS data model. Recursive pruning is used to reduce the size of both the conformational ensemble and the descriptor space until the TACS data model contains just enough information to determine probable conformation(s) of ligands bound to their protein targets. The TACS algorithm is comprised of five components: (1) conformational ensemble generation, (2) 3-D sensitive descriptor calculation, (3) ensemble descriptor preprocessing, (4) model generation, and (5) prediction of bound conformation(s). Significantly, this method precludes the need for subjective or objective molecular alignment. We report the application of this technique to five benchmark protein-ligand couples where the conformation of a bound ligand has been previously established using X-ray crystallography: 9-cis-retinoic (1) and 9-trans-retinoic acid (2), both agonists for the retinoic acid receptor gamma, compounds KH1060 (3) and MC1288 (4), which bind to the vitamin D3 receptor, and R04 (5), an inhibitor bound to human rhinovirus 14 thermolysin. The binding conformations predicted by TACS were compared to the crystallographic structures extracted from their respective binding sites using root-mean-squared deviation (rmsd) criteria. Three of the conformations found using TACS were within crystallographic error. 9-cis-Retinoic acid, 9-trans-retinoic acid, and MC1288, when superimposed on their crystallographic structures, gave rmsd values of 0.22, 0.17, and 0.34 A, respectively. The rmsd values for KH1060 (1.54 A) and R04 (1.01 A) were larger but still reasonable.